Is POMT1 p.Trp186Cys (c.558G>T) pathogenic?

POMT1 p.Trp186Cys (c.558G>T) is classified Uncertain significance in POMT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-17). AlphaMissense: likely pathogenic (0.8193); Ultra-rare (popmax 0.0285%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2K.

What condition is associated with POMT1 p.Trp186Cys (c.558G>T)?

POMT1 p.Trp186Cys (c.558G>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2K, muscular dystrophy-dystroglycanopathy, type A, muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 (ClinVar).

How common is POMT1 p.Trp186Cys (c.558G>T) in the general population?

POMT1 p.Trp186Cys (c.558G>T) is ultra-rare (popmax 0.0285%, sas) (gnomAD).

How is POMT1-related limb-girdle muscular dystrophy R11 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about POMT1 p.Trp186Cys (c.558G>T)?

AlphaMissense predicts likely pathogenic (score 0.8193) — an in-silico prediction, not a clinical call.

POMT1 p.Trp186Cys

c.558G>T · rs772370177 · VCV2154108

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8193 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2K

Computational evidence

Protein change
AlphaMissense	0.8193	likely pathogenic
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -13.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 19 kb · p 0.016 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0285% South Asian · 26/91,090 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00178% 26/1,461,886 alleles · ultra-rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: POMT1
Protein: p.Trp186Cys
Coding: c.558G>T
MANE Select: NM_001077365
dbSNP: rs772370177
Type: single nucleotide variant
Location: chr9:131509761 (GRCh38)
Gene constraint: LOEUF 1.002 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.09

Full POMT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2K — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy, type A muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

For POMT1-related limb-girdle muscular dystrophy R11 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

POMT1 p.Trp186Ter Pathogenic ★ same residue
POMT1 c.1175+1G>A Pathogenic ★★ same condition
POMT1 c.1176-2A>G Pathogenic/Likely pathogenic ★★ same condition
POMT1 c.1272+1G>A Pathogenic ★★ same condition
POMT1 c.1272+2T>C Pathogenic/Likely pathogenic ★★ same condition
POMT1 c.1698+1G>A Pathogenic/Likely pathogenic ★★ same condition
POMT1 c.229+2T>C Likely pathogenic ★★ same condition
POMT1 c.280+1G>T Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pomt1-p-trp186cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown